This invention relates to a composition of topical preparation containing alprostadil for the treatment of erectile dysfunction, which has excellent skin permeation rate with little skin irritation. Particularly, the present invention relates to a composition of topical preparation containing alprostadil, which is prepared by dissolving alprostadil itself or a solid dispersion thereof prepared using poloxamer, into a mixture of an oily vehicle, a pyrrolidone and an anti-irritant agent.
Erectile dysfunction refers to a condition of the inability to achieve and maintain penile erection sufficient to complete satisfactory sexual intercourse. There are two major causes for the erectile dysfunction: psychogenic and organic causes. Previously, erectile dysfunction was thought to be of psychogenic origin. In these days, however, it is believed that most of erectile dysfunction comes from organic causes resulting from damage in nerve, blood vessel or hormone system, surgery, or drug administration.
Erectile dysfunction can be cured with surgical or pharmacological means. For the pharmacological treatment, some effective drugs are available, orally or locally. As oral drugs, yohimbine and trazodone have been used, but their clinical effect is not pronounced. Recently, sildenafil, a selective inhibitor of phosphodiesterase, has been introduced into the market as an oral drug. This new oral drug showed positive result in the treatment of erectile dysfunction. However, the oral administration of a drug accompanies systemic side effects inevitably, since the drug reaches the site of action after it is distributed throughout the whole body by the systemic circulation. Sildenafil also has some systemic side effects such as headache, flushing, indigestion and changes in vision, etc. Particularly, it may cause a serious side effect, if taken by patient medicated with organic nitrates, due to the possibility of dramatic drop in blood pressure. Therefore, a local treatment is the method of choice for the treatment of erectile dysfunction, since it is a local disorder. For this purpose, alprostadil (prostaglandin E1), papaverine, or phentolamine has been used. Among them, alprostadil is demonstrated to be the most effective drug for the local treatment of erectile dysfunction. Until now, intracavernous injection and transurethral pellet of alprostadil are commercially available in the market. However, the injection formulation needs a direct injection to the penis. Thus, patients may feel uncomfortable, and a pain or bleeding, or even infection on the injected site may occur. The transurethral pellet also has inconvenience in inserting into urethra, and burning sense on urethra or pain on penis may occur.
As mentioned above, alprostadil shows excellent pharmacological effect in the treatment of erectile dysfunction when applied locally. However, these two invasive methods, intracavernous injection and transurethral delivery, are only available as currently available dosage forms even though a topical preparation is more convenient to apply than those methods. This is due to two problems in the formulation of alprostadil as a topical preparation. One is the instability of the drug in the conventional topical preparation which usually contains water in it. Like other prostaglandins, alprostadil is degraded easily to prostaglandin A1 or prostaglandin B1 in the presence of water. The other one is that the skin permeation rate of alprostadil itself is too low to achieve therapeutic drug concentration locally when applied topically.
The dosage forms for the topical application of alprostadil disclosed in patents include gels, ointments, creams without any detailed formula. Beside those dosage forms, U.S. Pat. Nos. 6,046,240 and 6,013,277 disclosed liposome for the formulation of topical preparations of alprostadil. However, all these dosage forms include water in them, which induces the degradation of alprostadil. As a dosage form which does not contain water, WO No. 99/66870, U.S. Pat. Nos. 5,380,760 and 5,741,511 disclosed transdermal patch for the topical delivery of alprostadil. However, transdermal patch has a critical drawback that it needs long time to delivery the drug underneath the skin enough to reach the therapeutic drug concentration locally. In addition, all of these patents do not mention any special enhancers for the skin permeation of alprostadil. On the other hand, U.S. Pat. Nos. 6,046,244 and 5,942,545 disclosed topical preparations of alprostadil which contain skin permeation enhancers. In U.S. Pat. No. 6,046,244, alkyl-2-(N,N-disubstituted amino)-alkanoate or (N,N-disubstituted amino)-alkanol alkanoate has been used as the skin permeation enhancer, and in U.S. Pat. No. 5,942,545, dioxolane, dioxane, or acetal. However, these enhancers are not commercially available and there are not sufficient information on the effects of these enhancers other than that as a skin permeation enhancer so far, since these are new materials. The present inventors had found that some pyrrolidones of pharmaceutical or cosmetic grade enhance the skin permeation of alprostadil, and filed a patent application for this invention (Korean Patent Application No. 99-31090). The excellent skin permeation of alprostadil was obtained with the preparation of this patent. Also, the stability of alprostadil in the preparation was highly improved, since the topical formulation in this patent is based on non-aqueous vehicles. However, the preparation in this patent has also a shortcoming of severe topical irritation on the applied area, which may be due to the drug itself or the excipients used or the combination of the two.
Through intensive research for a long time on the combination of oily vehicles, skin permeation enhancers and anti-irritant agents for the alprostadil, the present inventors discovered a composition of topical preparation containing alprostadil which has excellent skin permeation rate with little skin irritation to complete the present invention.
Therefore, an object of the present invention is to provide a composition of topical preparation containing alprostadil for the treatment of erectile dysfunction, which has excellent skin permeation rate with little skin irritation.